PROJECT SUMMARY With 35 million people living with HIV/AIDS (including 1.2 million in the US), and 1.2 million AIDS-related deaths in 2014, HIV/AIDS remains a formidable global epidemic (UNAIDS, CDC). Modern HIV therapy combines drugs from different classes to form ?cocktail? therapies that have transformed HIV into a manageable chronic infection for many individuals. Despite the effectiveness of these drugs, side effects and drug resistance remain serious concerns for these life-long therapies. Thus, there is an enduring need for novel HIV inhibitors with new mechanisms of action and stronger barriers to resistance. Furthermore, it is recognized that lack of patient compliance is a major factor leading to treatment failure. For this reason, HIV specialists are excited by the prospect of long-acting therapies, and a cocktail of such therapies would provide a revolutionary new treatment option for many HIV patients. Navigen is a small pharmaceutical company targeting infectious diseases through an innovative discovery and design process. We have identified a novel HIV entry inhibitor, cholesterol-PIE12-trimer (cPIE12-trimer), that is a protease-resistant D-peptide (peptide made from D-amino acids) that targets HIV's conserved entry machinery. With highly potent activity against all major subtypes of HIV and an unprecedented barrier to resistance, our anti-HIV D-peptide overcomes the current limitations of the entry inhibitor treatment class. In addition, cPIE12-trimer is also ideal for pre-exposure prophylaxis since it blocks the first stage of the viral lifecycle prior to infection of target cells. cPIE12-trimer is currently in late preclinical development at Navigen. cPIE12-trimer's uniquely conserved target, superior resistance profile, high potency, protease resistance, and favorable pharmacokinetic (PK) and physicochemical properties make it an ideal candidate for long-acting depot formulation. In this two-year grant application, we will work with an industry-leading formulation group at DURECT to develop a sustained-release (depot) formulation of cPIE12-trimer suitable for once-monthly administration via subcutaneous injection. Additionally, we will perform rat and non-human primate PK studies on candidate depot formulations. Demonstration of sustained therapeutic drug levels for one month in NHPs given depot-formulated cPIE12-trimer, in combination with our recent demonstration of PrEP efficacy in a stringent SHIV NHP model, will greatly facilitate development partnerships to advance a depot-formulated cPIE12-trimer through IND filing and clinical trials. Once-monthly cPIE12-trimer would provide a potentially transformative new option for the prevention and treatment of HIV, especially if used in combination with other sustained-release HIV inhibitors in development.